Polymers have enjoyed increasing use in medical applications in recent years. Such polymers, which can be synthetic materials or may be derived from natural sources, have been employed for applications as diverse as delivery of therapeutic agents, e.g., drugs, in time-release formulations; reconstruction of tissue defects (for example, in plastic surgery); protection of damaged tissues; prevention of post-surgical adhesions; and the like.
Post-surgical adhesions are caused by a combination of factors including manipulative trauma and drying of the tissues during the surgery itself. A number of techniques attempting to ameliorate these problems have been described. Highly concentrated solutions of a number of polymers have been used to coat the surgical area before, and during, surgery so as to minimize the drying and act as "cushion" to prevent some of the manipulative trauma. Examples of these techniques are described in U.S. Pat. No. 4,819,617, to Goldberg et al., U.S. Pat. No. 4,886,787 to De Belder et al., and the above-referenced co-pending U.S. patent application Ser. No. 08/436,770. Among the materials used included polyvinylpyrrolidone, dextrans, carboxymethylcelluloses, and a number of other polymers such as protein or polypeptide solutions. One promising polymer which has been used is hyaluronic acid ("HA"). A series of patents by Goldberg et al., particularly U.S. Pat. No. 5,080,893 and U.S. Pat. No. 5,140,016, show the use of pretreatment of surgical sites with hyaluronic acid solutions as a means of preventing surgical adhesions.
Hyaluronic acid has several problems associated with its use. One problem with using hyaluronic acid is its cost. Hyaluronic acid can be obtained from rooster combs or human umbilical cords, and requires substantial purification to make pure enough to use in surgical techniques. See, e.g., U.S. Pat. No. 4,141,973, to Balazs, which describes methods of purifying hyaluronic acid. Hyaluronic acid can also be obtained in recombinant form, but is expensive. Even if the high cost and/or difficulties in purification can be justified, hyaluronic acid can have proteins associated with it which may cause tainting of the open surgical wound.
A variety of polymers have been employed as drug delivery systems, e.g., for slow release of therapeutic agents. Polymeric drug delivery systems generally are of two types: polymers which physically entrap a drug, and polymers to which a therapeutic agent is chemically linked. In the former case, the drug is released by gradual diffusion from the polymer matrix as the matrix breaks down or is degraded, while in the latter polymers, the drug is chemically released from the polymer. Such slow-release polymers can be administered to a subject, e.g., by injection or implantation, to provide drug therapy for a prolonged period. Slow-release polymers are convenient because depot dosing increases patient compliance with the drug regimen, reducing or eliminating the need for repeated drug administration. In addition, a slow-release polymer formulation can be implanted in a discrete organ or tissue, which in some cases provides localized therapeutic action of the released drug while decreasing systemic side effects.
Chitin, the primary building block of the shells of crustaceans and many insects, has been modified for use as a polymer in medical applications. Chitin can be obtained relatively inexpensively, primarily from waste products which might otherwise be discarded. U.S. Pat. No. 4,619,995, issued on an application by Hayes, describes a novel derivative of chitin, NOCC. NOCC has carboxymethyl substitutes on some of both the amino and hydroxyl sites of the glucosamine units of the chitosan structure and can be used in an uncrossed linked form as a solution; it can be cross-linked or complexed into a stable gel. For example, in the NOCC compositions of Hayes, the degree of substitution was typically less than one, with a distribution of hydroxyl to amino substitution of approximately 2:1. Thus, approximately 50% of the amino groups of the NOCC material of Hayes are not substituted with carboxymethyl groups (see also U.S. Pat. No. 5,412,084 to Elson et al.) Because of its advantageous physical properties, and its relative low cost compared with materials like hyaluronic acid, NOCC presents advantageous properties for use in applications such as surgical techniques.
Previously-described methods for crosslinking NOCC have, however, suffered from certain disadvantages. For example, NOCC has been covalently crosslinked through the use of bifunctional reagents such as glyoxal, in which each of the two aldehyde groups of glyoxal reacts with an amino group of NOCC, resulting in a crosslinked product (see, e.g., the above-referenced U.S. Pat. No. 4,619,995). This product includes the 2-carbon backbone of glyoxal as a covalently-bonded bridging moiety of the crosslinked adduct; this bridging moiety cannot readily be removed from the crosslinked NOCC without destroying the crosslinked NOCC. NOCC has also been ionically crosslinked, e.g., by addition of a cation such as divalent calcium, to form gels. However, ionically cross-linked NOCC gels have only moderate stability, e.g., to heat or solvents, and can dissolve in aqueous solutions.
Accordingly, it is an object of the present invention to provide covalently linked NOCC in which no bridging moiety is present.
It is a further object of the invention to provide a derivative of NOCC in which a therapeutic agent is releasably bound to, or entrapped by, NOCC, to provide a sustained release compound comprising NOCC and a therapeutic agent.
It is a further object of the invention to provide crosslinked NOCC in which linking occurs through a bond between a carboxyl group of a N,O-carboxymethylchitosan chain and an amino group of a N,O-carboxymethylchitosan chain.
It is still a further object of the invention to provide methods for wound management by administering linked NOCC to a subject.
It is another object of the invention to provide methods for preventing post-surgical adhesions by administering linked NOCC to a subject.
It is yet a further object of the invention to provide methods for administering a therapeutic agent to a subject by administering to the subject a composition comprising NOCC and a therapeutic agent.
These and other objects, features, and advantages of the invention will be apparent from the following description and claims.